Metalloproteinase Inhibitors
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumors, angiofibromas and hemangiomas.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ion at the active site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (L. M. Matrisian, Trends in Genetics, 1990, 6, 121-125).
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage site in the collagen molecule. A recent paper by Chapman et al (J. Med. Chem. 1993, 36, 4293-4301) reports some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonic acid) groups.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group and a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (IA) ##STR2## in which X is the zinc binding hydroxamic acid (--CONHOH) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. The following patent publications disclose hydroxamic acid-based and/or carboxylic acid-based MMP inhibitors:
U.S. Pat. No. 4599361 (Searle) PA1 EP-A-2321081 (ICI) PA1 EP-A-0236872 (Roche) PA1 EP-A-0274453 (Bellon) PA1 WO 90/05716 (British Bio-technology) PA1 WO 90/05719 (British Bio-technology) PA1 WO 91/02716 (British Bio-technology) PA1 WO 92/09563 (Glycomed) PA1 U.S. Pat. No. 5183900 (Glycomed) PA1 U.S. Pat. No. 5270326 (Glycomed) PA1 WO 92/17460 (SmithKline Beecham) PA1 EP-A-0489577 (Celltech) PA1 EP-A-0489579 (Celltech) PA1 EP-A-0497192 (Roche) PA1 U.S. Pat. No. 5256657 (Sterling Winthrop) PA1 WO 92/13831 (British Bio-technology) PA1 WO 92/22523 (Research Corporation Technologies) PA1 WO 93/09090 (Yamanouchi) PA1 WO 93/09097 (Sankyo) PA1 WO 93/20047 (British Bio-technology) PA1 WO 93/24449 (Celltech) PA1 WO 93/24475 (Celltech) PA1 EP-A-0574758 (Roche) PA1 WO 94/02447 (British Biotech) PA1 WO 94/02446 (British Biotech) PA1 R.sub.1 represents the characterizing side chain of a natural or non-natural alpha amino acid, in which any functional group present may be protected; PA1 R.sub.2 represents (i) a group Z.sup.1 --Q--W--, or (ii) (Z.sup.1 --Q--W--).sub.2 CH-- in which each of the two groups Z.sup.1 --Q--W-- present may be the same or different, and wherein in both cases (i) and (ii): PA1 Y represents a carbonyl (--C(.dbd.O)--) or sulphonyl (--(SO.sub.2)--) group; PA1 Z represents PA1 R.sub.2 represents (i) a group Ar--Q--W-- in which Ar represents optionally substituted aryl or heteroaryl, Q represents a bond or --O-- or S--, and W represents a divalent C.sub.1 -C.sub.20 straight or branched chain alkyl moiety which may carry one or more substituents selected from OH, OMe, halogen, NH.sub.2, NMeH, NMe.sub.2, CO.sub.2 H, CO.sub.2 Me, COMe, CHO, CONH.sub.2, CONHMe, CONMe.sub.2, CH.sub.2 OH, NHCOMe; (ii) heterocyclyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl (C.sub.1 -C.sub.6)alkyl or cycloalkenyl(C.sub.1 -C.sub.6)alkyl group; or (iii) a linear saturated or unsaturated C.sub.2 -C.sub.20 hydrocarbon chain, which chain PA1 provided that the maximum length of the chain is no more than 28 C, O, S and N atoms; and PA1 Z represents: PA1 R.sub.2 represents a phenyl(C.sub.1 -C.sub.6)alkyl, heterocyclyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl (C.sub.1 -C.sub.6)alkyl or cycloalkenyl(C.sub.1 -C.sub.6)alkyl group, or a linear saturated or unsaturated C.sub.2 -C.sub.20 hydrocarbon chain, which chain PA1 provided that the maximum length of the chain is no more than 28 C, O, S and N atoms; and PA1 Z represents: PA1 (a) a hydrocarbon group --CR.sub.9 R.sub.10 R.sub.11 in which each of R.sub.9, R.sub.10 and R.sub.11 is independently hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl; or R.sub.9 and R.sub.10 together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or R.sub.9, R.sub.10 and R.sub.11 together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); PA1 or (b) a group --CR.sub.12 R.sub.13 R.sub.14 in which each of R.sub.12 and R.sub.13 is independently (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, O(C.sub.1 -C.sub.6) alkyl, S(C.sub.1 -C.sub.6) alkyl, OH, SH, OPh, OCH.sub.2 Ph, SPh, SCH.sub.2 Ph, halogen, CN, CO.sub.2 H, (C.sub.1 -C.sub.4)perfluoroalkyl, CH.sub.2 OH, CO.sub.2 (C.sub.1 -C.sub.6)alkyl, or a group phenyl or heteroaryl which is optionally substituted by one or more substituents independently selected from hydrogen, hydroxyl, halogen, CN, CO.sub.2 H, CO.sub.2 (C.sub.1 -C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1 -C.sub.6)alkyl, CONH(C.sub.1 -C.sub.6 alkyl).sub.2, CHO, CH.sub.2 OH, (C.sub.1 -C.sub.4)perfluoroalkyl, O(C.sub.1 -C.sub.6)alkyl, S(C.sub.1 -C.sub.6)alkyl, SO(C.sub.1 -C.sub.6)alkyl, SO.sub.2 (C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, NH(C.sub.1 -C.sub.6)alkyl, N((C.sub.1 -C.sub.6)alkyl).sub.2, NHCO(C.sub.1 -C.sub.6)alkyl C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.3 -C.sub.8)cycloalkyl, C.sub.4 -C.sub.8)cycloalkenyl, phenyl or benzyl; and R.sub.14 is hydrogen, OH, SH, OPh, OCH.sub.2 Ph, SPh, SCH.sub.2 Ph, halogen, CN, CO.sub.2 H, (C.sub.1 -C.sub.4)perfluoroalkyl, CH.sub.2 OH, CO.sub.2 (C.sub.1 -C.sub.6)alkyl, or a group phenyl or heteroaryl which is optionally substituted by one or more substituents independently selected from hydrogen, hydroxyl, halogen, CN, CO.sub.2 H, CO.sub.2 (C.sub.1 -C.sub.6)alkyl, CONH.sub.2, CONH(C.sub.1 -C.sub.6)alkyl, CONH(C.sub.1 -C.sub.6 alkyl).sub.2, CHO, CH.sub.2 OH, (C.sub.1 -C.sub.4)perfluoroalkyl, O(C.sub.1 -C.sub.6)alkyl, S(C.sub.1 -C.sub.6)alkyl, SO(C.sub.1 -C.sub.6)alkyl, SO.sub.2 (C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, NH(C.sub.1 -C.sub.6)alkyl, N((C.sub.1 -C.sub.6)alkyl).sub.2, NHCO(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.3 -C.sub.8)cycloalkyl, C.sub.4 -C.sub.8)cycloalkenyl, phenyl or benzyl; or R.sub.12 and R.sub.13 together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring, PA1 C atom carrying the R.sub.1 and X group=R, but mixtures in which the above configuration predominates are also contemplated. PA1 R.sub.1 may be for example hydrogen; a (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, phenyl, substituted phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, substituted phenyl(C.sub.1 -C.sub.6)alkyl, heterocyclyl, substituted heterocyclyl, heterocyclyl(C.sub.1 -C.sub.6)alkyl, or substituted heterocyclyl(C.sub.1 -C.sub.6)alkyl group; a group BSO.sub.n A-- wherein n is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6)alkyl, phenyl, substituted phenyl, heterocyclyl, substituted heterocyclyl, (C.sub.1 -C.sub.6)acyl, phenacyl or substituted phenacyl group, and A represents (C.sub.1 -C.sub.6)alkyl; an aryl(C.sub.1 -C.sub.6)alkyl group; an amino(C.sub.1 -C.sub.6)alkyl; hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or carboxy(C.sub.1 -C.sub.6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated; or a (C.sub.1 -C.sub.6)alkyl group substituted by maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo-1H-benzd,e!isoquinol-2-yl, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino. Specific examples of R.sub.1 groups include hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, cyclohexyl, phenyl, hydroxymethyl, 2-methoxyethyl, 2-methylthioethyl, 2-methylsulphonylethyl, 4-(N,N-dimethylamino)butyl, 4-(N,N-dimethylglycylamino)butyl, allyl, methoxymethyl, phenylmethyl, phthalimidomethyl, 2-phthalimidoethyl, 4-morpholinoethyl, 4-thiomorpholinoethyl, 2-methylthiazol-4-ylmethyl, tetrazol-5-ylmethyl, 6-chloropiperonyl, 1-pyrazolylmethyl, pyrid-3-ylmethyl, 1-methyl-4-imidazolylmethyl, N-methylpyrid-4-yl, 2-(pyrid-3-yloxy)ethyl, methylthiomethyl, benzylthiomethyl or thienylsulphanylmethyl. Presently preferred are compounds in which R.sub.1 is hydrogen, methyl or phenylmethyl. PA1 In compounds of the invention in which Z is not a group of formula (III) and Y is sulphonyl or carbonyl, examples of Z groups include any of those specifically listed above for R.sub.2, in particular hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-pentadecyl, n-hexadecyl, or benzyl. Presently preferred are n-hexadecyl, n-octyl, n-butyl, n-propyl, and benzyl. PA1 In compounds of the invention in which Z is not a group of formula (III) and Y is carbonyl, examples of Z groups include, in addition to those specified in the preceding paragraph, phenyl, 4-methylphenyl, 4-tert-butylphenyl, 3-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-aminophenyl, 4-N,N-dimethylaminophenyl, 2,4,6-trimethylphenyl, 2,4,6-isopropylphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-ethoxyphenyl, 4-n-hexyloxyphenyl, 4-n-butyloxyphenyl, 4-(2-methylbutyloxyphenyl, 4-n-heptyloxyphenyl, 4-benzyloxyoxyphenyl, 4-isopropyloxyphenyl, 4-ethoxyethoxyphenyl, 2.3-dihydrobenzofuran-5-yl, 1-napthyl, 2-napthyl, 2-thienyl or 2-acetamido-4-methyl-thiazol-5-yl, 3,5-dimethylisoxazol-5-yl, and 2,4-dimethylisoxazol-5-yl. PA1 For compounds in which Z is a group of formula (III): PA1 2-Benzyl-(octane-1-sulfonyl)-amino!-N-hydroxy-acetamide, PA1 N-Hydroxy-2-(2-methoxy-benzyl)-(octane-1-sulfonyl)-amino!-acetamide, PA1 2-(2-Ethoxy-benzyl)-(octane-1-sulfonyl)-amino!-N-Hydroxy-acetamide, PA1 N-Hydroxy-2-(naphthalen-2-yl-methyl)-(octane-1-sulfonyl)-amino!-acetamide, PA1 2-(4-Chloro-benzyl)-(octane-1-sulfonyl)-amino!-N-hydroxy-acetamide, PA1 (a) causing an acid of general formula (IV) ##STR6## or an activated derivative thereof to react with hydroxylamine, O-protected hydroxylamine, N,O-diprotected hydroxylamine, or a salt thereof, R.sub.1, R.sub.2, Y and Z being as defined in general formula (II) except that any substituents in R.sub.1, R.sub.2, Y and Z which are potentially reactive with hydroxylamine, O-protected hydroxylamine, N,O-diprotected hydroxylamine or their salts may themselves be protected from such reaction, then removing any protecting groups from the resultant hydroxamic acid moiety and from any protected substituents in R.sub.1, R.sub.2, Y and Z; or PA1 (b) deprotecting a diprotected hydroxamic acid derivative of formula (IVa) ##STR7## in which R.sub.1, R.sub.2, Y and Z are as defined in general formula (II),R.sub.14 is an amino protecting group and R.sub.15 is a hydroxyl protecting group.